first order rate constant of appearance/disappearance of tolerance
described in: Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects Shi J, Benowitz NL, Denaro CP and Sheiner LB. ; Clin. Pharmacol. Ther. 1993 Jan;53(1):6-14. PMID: 8422743 ; Abstract: We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90 percent reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine. Caffeine intake in this version is modelled as cups of coffee drunk at regular intervals (parameter t_interval ). The amount of caffeine per cup is determined by the parameter cupsize . The body weight of the person drinking is given by the parameter bodyweight . The even coffee cup occures delayed to the drinking of each cup, as the availability of the caffeine in the digestive tract is assumed to be delayed to the ingestion by the time t_lag . This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
peripheral to central compartment transport rate
apparent volume of the central compartment per kg body-weight
overall clearance per kilogram bodyweight
the central compartment, corresponding mainly to the plasma. Its apparant volume is given by the parameterV_C
intervall between drinking of cups of coffee
time lag between drinking of coffee and arrival in gastrointestinal tract
virtual compartment to account for tolerance effects
first order rate of entry/exit to/from effector site
availability of caffeine in gut after drinking a cup
hypothetical antagonistic metabolite to account for tolerance development